Neural correlates of emotion regulation deficits in remitted depression: The influence
of regulation strategy, habitual regulation use, and emotional valence
Philipp Kanskea,b,⁎, Janine Heisslerb,c, Sandra Schönfeldera,b, Michèle Wessaa,b
aSection for Experimental Psychopathology and Neuroimaging, Department of General Psychiatry, Center for Psychosocial Medicine, Heidelberg University, Germany
bDepartment of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
cCenter for Doctoral Studies in Social and Behavioral Sciences, Graduate School of Economic and Social Sciences, University of Mannheim, Germany
a b s t r a c t a r t i c l ei n f o
Accepted 30 March 2012
Available online 10 April 2012
Anterior cingulate cortex
Regulating emotions through reappraisal has been shown to elicit abnormal neural activation patterns in
currently depressed patients. It is, however, unclear if this deficit generalizes to other emotion regulation
strategies, if it persists when patients recover, and if it is related to habitual use of reappraisal strategies.
Therefore, we measured the neural responses to emotional images with functional magnetic resonance
imaging in remitted patients with previous episodes of major depression and healthy controls. While viewing
the images participants regulated the elicited emotions using either a reappraisal or a distraction strategy.
Habitual reappraisal use was measured with the Cognitive Emotion Regulation Questionnaire. Depressed
patients showed a selective deficit in down-regulating amygdala responses to negative emotional stimuli
using reappraisal. This down-regulation of amygdala activity was strongest in participants high in habitual
reappraisal use. Activity in the regulating control-network including anterior cingulate and lateral orbitofron-
tal cortex was increased during both emotion regulation strategies. The findings in remitted patients with
previous episodes of major depression suggest that altered emotion regulation is a trait-marker for
depression. This interpretation is supported by the relation of habitual reappraisal use to amygdala down-
© 2012 Elsevier Inc. All rights reserved.
Altered affective processing is one of the defining characteristics of
major depressive disorder (MDD). Its neural signature includes hyperac-
tivity in a number of brain structures involved in emotion detection and
generation (Drevets et al., 2002; Sheline et al., 2001). A critical question
is whether the altered emotional responsivity in MDD is mirrored by im-
paired regulation of emotion. In contrast to a relatively large number of
only little evidence regarding the non-automatic cognitive control of
emotions tested through explicit instructions to regulate current affect.
The few data on cognitive control of emotions suggest a deficit in the ca-
and prefrontal control regions (Erk et al., 2010; Johnstone et al., 2007).
Four major questions arise from these studies.
First, the specific cognitive regulation strategy that previous studies
applied was reappraisal, which requires participants to reinterpret the
meaning of emotional stimuli yielding them less negative and arousing
(Gross, 2001). It is unclear, however, if the deficit in cognitive emotion
regulation is restricted to reappraisal or generalizes to other emotion
regulation strategies. Recent evidence in healthy participants demon-
recruit overlapping, but distinct neural networks. While both strategies
activated dorsolateral prefrontal (dlPFC) and parietal cortices, orbito-
frontal cortex (OFC) activation was specific to using reappraisal, while
distraction yielded more extensive activation in parietal and dorsome-
dial prefrontal/anterior cingulate cortex (dmPFC, ACC; Kanske et al.,
2011; McRae et al., 2010). The tested strategies also differed in their ef-
fectiveness in amygdala down-regulation, with distraction yielding
stronger and more extended down-regulation of the amygdala activity.
The specific networks involved in emotion regulation have been shown
to be differentially affected in depression. Lateral parts of the OFC show
as well as hypoactivation have been reported (Disner et al., 2011;
Wagner et al., 2006). Increased activation in control regions has been
interpreted as a compensatory mechanism, which might also apply
for emotion regulation in depression (Wagner et al., 2006). Further-
more, a recent meta-analysis showed structural changes in depression
to be located more consistently in the OFC (Arnone et al., 2012). We,
therefore, asked if emotion regulation deficits in depressed patients
might differ between strategies.
NeuroImage 61 (2012) 686–693
⁎ Corresponding author at: Section for Experimental Psychopathology and Neuroim-
aging, Department of General Psychiatry, Center for Psychosocial Medicine, University
Clinic Heidelberg, Germany. Fax: +49 6221 56 5374.
E-mail address: firstname.lastname@example.org (P. Kanske).
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Second, as previous studies investigated emotion regulation in cur-
rently depressed but not remitted patients (Beauregard et al., 2006;
sists when patients recover. Because of high relapse rates (Hardeveld
et al., 2010), remission is a vulnerable clinical state also characterized
by greater sensitivity to mood challenges that predict recurrence
tivation patterns (Liotti et al., 2002). It remains to be investigated if al-
tered regulation of emotion also reflects a trait-marker for depression
and is not necessarily linked to present symptoms.
ences in the use of emotion regulation through reappraisal. A recent
sion (Aldao et al., 2010). Interestingly, habitual reappraisal use is also
related to incremented emotional responding in currently remitted pa-
tients (Joormann and Gotlib, 2010). Nevertheless, it still needs to be
tested if these habitual differences are related to impaired amygdala
regulation during reappraisal use in neuroimaging experiments.
Fourth, previous studies concentrated on the down-regulation of
negative emotion (Beauregard et al., 2006; Erk et al., 2010; Johnstone
et al., 2007), which may be suggestive because of the excess of negative
emotion in depression. Nevertheless, it is unclear if the deficit is selec-
tive to negative emotion or generalizes to positive emotion as well.
To address these questions, we examined two different cognitive
emotion regulation strategies, reappraisal and distraction, in pa-
tients with previous depressive episodes currently in remission.
While reappraisal is a form of cognitive change of emotion, distrac-
tion requires attentional control to divert attention to the perfor-
mance of a parallel task, reducing the resources available for
emotional processing (Ochsner and Gross, 2005). To differentiate
the control of negative and positive emotion we used pictures of dif-
ferent valence and measured neural responses while patients ap-
plied emotion regulation with functional magnetic resonance
imaging (fMRI). We also assessed habitual differences in the use of
reappraisal using a validated questionnaire (Garnefski and Kraaij,
2007). This allowed testing four major hypotheses. First, if the defi-
cits in regulating emotions are specific to the reappraisal strategy,
than application of the distraction strategy should not yield any dif-
ferences between healthy participants and MDD patients. Candidate
regions for alterations include the amygdala as the major site for reg-
ulation effects, and the OFC and ACC/dmPFC as part of the control
networks for reappraisal and distraction, respectively. In the amyg-
dala we expect impairments to show in reduced down-regulation
of activity in depression. In contrast, in line with the concept of com-
pensatory hyperactivation, patients should show an activation in-
crease in control regions. Second, if emotion regulation deficits are
a trait-marker for depression we expect to also observe this in remit-
ted MDD patients. Third, we expect to find a relation of neural activa-
tion changes during emotion regulation to habitual use of emotion
regulation. Fourth, as depression is mainly characterized by exces-
sive negative emotion, the deficits should be specific to down-
regulating negative, but not positive emotion.
Demographic and clinical characteristics for patients with major depressive disorder (MDD) and healthy control participants (HC).
HC MDDStatistics p-value
Gender ratio (female/male)
Age. Mean (SD)
Years of education. Mean (SD)
Intelligence score. Mean (SD)
% married lifetime
% currently employed
Handedness: LQ-Scores. mean (SD)
HAMD. Mean (SD)
ADS. Mean (SD)
BDI. Mean (SD)
BDI. Affective subscale. Mean (SD)
BDI. Somatic subscale. Mean (SD)
Current medication [subjects (n); duration (months). mean (SD)]
Antidepressant — SSRI
Antidepressant — SSNRI
Antidepressant — tricyclic
Medication load. mean (SD) #
Persons regularly consuming caffeine. No. (%)
Persons regularly consuming nicotine. No. (%)
Persons regularly consuming alcohol. No. (%)
Age at onset of disease. Mean (SD) age
Age at first hospitalization. Mean (SD) age +
Number of previous hospitalizations. Mean (SD)
Number of past depressive episodes. mean (SD)
Time since last depressive episode (months)
3; 61.33 (49.98)
3; 29.67 (18.01)
4; 88.75 (36.13)
3; 73.5 (44.7)
4; 47 (16.75)
# calculated according to Sackeim (2001).
+ calculated with N=15 as 8 patients had not been hospitalized.
P. Kanske et al. / NeuroImage 61 (2012) 686–693
Material and methods
Twenty-six remitted patients with MDD and 26 healthy controls
(HC), matched for age, sex, handedness, and education participated
in the study. Three patients and one control had to be excluded
from the analysis due to technical problems at the time of measure-
ment or excessive movement artifacts in the fMRI data, leaving
N=23 remitted patients with major depression and 25 controls for
data analyses (see Table 1 for demographic and illness-related char-
acteristics of the final sample).
Patients were recruited at the Central Institute of Mental Health
(Mannheim, Germany) and through local psychotherapists, psychia-
trists and patient support groups. DSM-IV diagnoses of major depres-
sion and potential comorbid mental disorders were assessed with the
German version of the Structured Clinical Interview for DSM-IV, SCID-
I and -II (First et al., 1997), conducted by trained psychologists. None
of thepatients currentlyfulfilledthe criteriafor any othermentaldisor-
der. Remission from a depressive episode was defined as a score below
5 onthe Hamilton Depression Rating Scale (Hamilton, 1960) for atleast
8 weeks. At the time of the scan, 9 patients were taking antidepressant
medication (see Table 1). Medication load was calculated according to
Sackeim (2001) and included as a covariate in all analyses.
Healthy participants were recruited through the registry office of
the city of Mannheim and advertisement in public facilities. They
were free of past or present mental disorder according to DSM-IV.
Exclusion criteria for all participants were any history of neurolog-
ical disorder, head trauma with loss of consciousness, metal implants
or large tattoos with metal containing color, current and lifetime sub-
stance abuse or dependence and age below 18 or above 65 years.
All participants gave informed written consent. The study was ap-
proved by the local ethics committee (Medical Faculty Mannheim,
University of Heidelberg).
Experimental paradigm and procedure
The details of the experimental paradigm (see Fig. 1) have been
described elsewhere (Kanske et al., 2011). In short, participants
were presented with emotional (16 negative, 16 positive, highly
arousing) and neutral (16 low arousing) images (from the In-
ternational Affective Picture System, IAPS; Lang et al., 2005)
and required to simply view the pictures (view condition) or
to down-regulate the emotional response by either reappraising
the meaning of the stimuli (reappraisal condition) or by distraction
from the images by solving an arithmetic task (distraction condi-
tion). Each picture was presented once in each condition (except
for neutral images, which were not presented in the reappraisal
condition) yielding 128 pseudo-randomly presented trials. Instruc-
tions regarding the condition were displayed after an initial emo-
tion induction phase (1 s) as a semi-transparent overlay on the
images. The regulation phase (6 s) was followed by a rating of par-
ticipants' current emotional state on a 9-point scale using the Self-
Assessment Manikins ranging from unpleasant to pleasant (4 s).
Six training trials were presented prior to the experiment, to fa-
miliarize participants with the procedure and practice the emotion
regulation strategies. Before the experiment started, the experi-
menter ensured that reappraisal strategies were employed as
intended by inquiring participants about the strategies they used.
To ensure that patients and controls perceived images similarly
emotional, all participants rated each image in arousal and valence
after the experiment, again using the 9-point scale and the Self-
Assessment Manikins. In addition, participants rated the difficulty and
effort required for each condition, to ensure that different results for
MRI data acquisition
MRI data were collected on a 3 T scanner (Magnetom TIM Trio, Sie-
mens Medical Solutions, Erlangen, Germany) at the Central Institute of
Mental Health, Mannheim. A high-resolution T1-weighted 3D image was
acquired (slice thickness=1.1 mm, FOV=256 mm×256 mm×256 mm,
matrix=256×256×256). Functional images were obtained from 40
A single shot echo planar sequence with parallel imaging GRAPPA-
technique (acceleration factor 2) was used with a TR of 2700 ms, a flip
angle of 90°, TE=27 ms, FOV=220×220 mm2, matrix=96×96, and a
slice gap of 0.7 mm.
fMRI data analysis
Image processing and statistical analysis was done with SPM8
(http://www.fil.ion.ucl.ac.uk/). Functional images were realigned,
slice-time corrected, and spatially normalized using the Montreal
Neurological Institute (MNI) template. For normalization images
were resampled every 3 mm using sinc interpolation. Images were
smoothed using a 9×9×9 mm Gaussian kernel.
Individual participants' data were analyzed using a General Linear
Model for blood oxygen level dependent (BOLD) signal changes due
to the experimental conditions. Movement parameters calculated dur-
ing realignment were included as parameters of no interest. Individual
statistical parametric maps were calculated to elucidate: (1) the emo-
negative and distraction positive vs. view positive), and (3) the reap-
praisal effect (reappraisal negative vs. view negative and reappraisal
positive vs. view positive).
Two types of second-level random-effects analyses were conducted:
ual contrast images for patients and controls separately. (2) To evaluate
differences between patients and controls, two-sample t-tests were
computed for all the contrasts.
For all analyses, anatomically defined regions of interests (ROI)
from the automated anatomical labeling atlas in WFU PickAtlas v2.0
Fig. 1. Sequence of events in a trial. The example pictures resemble those in the exper-
iment, but are not part of the IAPS. Adapted from Kanske et al. (2011), by permission of
Oxford University Press.
P. Kanske et al. / NeuroImage 61 (2012) 686–693
(Tzourio-Mazoyer et al., 2002) were used to examine activations in
the amygdala and the regulation networks as defined in our previous
investigation of reappraisal and distraction (Kanske et al., 2011).
These included middle and inferior OFC, dlPFC (middle frontal
gyrus), dmPFC (superior medial cortex), ACC, and parietal cortices
(inferior and superior parietal cortex). Activations were thresholded
at FWE-corrected pb.05. Medication load was included as a covariate
of no interest in all analyses including patients.
Statistical analyses of behavioral data
The emotional state ratings during the experiment were analyzed
with PASW (Version 18.0.1, SPSS Inc., Chicago, IL). A one-way ANOVA
was conducted to analyze the effect of the emotional picture presenta-
tion (negative, neutral, positive) on emotional state in the viewing con-
dition. A 2×3×2 repeated-measures ANOVA including the factors
emotion (negative, positive), task (distraction, view, reappraisal), and
group (MDD, HC) was calculated to elucidate the effects of regulation
on emotional state. The neutral condition was neglected for the second
analysis as there were no neutral pictures in the reappraisal condition.
The arousal and valence ratings of the pictures after the experiment
were analyzed with one-way repeated measures ANOVAs. All effects
with a pb.05 were treated as statistically significant.
Post-experimental valence and arousal rating
The rating of the images after the regulation experiment yielded the
same pattern as the normative IAPS ratings (see supplemental data
ST1). Negative and positive pictures were rated as more arousing than
neutral pictures (F(1,46)=90.2, pb.001; F(1,46)=125.0, pb.001, re-
sets (positive>neutral>negative; F(1,46)=293.3, pb.001; F(1,46)=
113.9, pb.001, respectively). There were no differences between MDD
patients and HCs (all p>.45).
Online valence rating
Analysis of the emotional state ratings after each trial (see Fig. 2)
revealed a significant main effect of emotion in the viewing condition
(F(2,90)=125.8, pb0.001). Planned comparisons showed that nega-
tive and positive trials differed from neutral trials indicating success-
ful emotion induction (negative vs. neutral: F(1,45=227.7, pb0.001;
positive vs. neutral: F(1,45)=94.9, pb0.001). There were no differ-
ences between MDD patients and HCs (all p>.46).
The second analysis regarding the regulation effects showed sig-
nificant main effects of emotion (F(1,90)=238.8, pb0.001) and task
(F(1,90)=7.4, pb.01), and an interaction of emotion and task
(F(2,180)=56.4, pb0.001). Repeated contrasts regarding the interac-
tion indicated that emotional pictures were rated less negative or
positive during distraction and reappraisal compared with the view
condition (all pb.001). There were no differences between MDD pa-
tients and HCs (all p>.40).
The ratings of effort and difficulty of the two regulation tasks
yielded no significant differences between conditions and no differ-
ences between MDD patients and HCs (all p>.45)
Within-group analyses largely replicated our previous findings in
both groups (see Kanske et al., 2011), for a complete list of activations
see supplemental data ST2). Emotional stimuli elicited increased
amygdala activity in comparison to neutral images, which was re-
duced when participants regulated emotion through either reapprai-
sal or distraction. This reduction was not significant for negative
emotional stimuli in MDD patients. The regulation conditions
recruited fronto-parietal control networks including dlPFC, and parie-
tal cortex, as well as dmPFC and anterior cingulate for distraction and
OFC for reappraisal.
Group comparisons yielded no differences for the contrast of
viewing emotional vs. neutral images. However, we found increased
left amygdala activation for negative emotional stimuli in the reap-
praisal contrast when comparing MDD patients to HCs (see Fig. 3),
indicating that patients were less successful in down-regulating
amygdala activity to negative pictures using reappraisal. We did
not find this pattern for positive emotional stimuli or for the dis-
traction condition. We also observed altered activity in the regula-
tory networks. Activation in the right OFC was increased in MDD
Fig. 2. Emotional state ratings during the experiment. The means of SAM-valence-
rating are displayed.
Fig. 3. (A) Increased activation in the left amygdala (x=−15, y=−1, z=−14,
Cs=18, T=3.07, Z=2.91) for MDD patients compared to healthy controls in the reap-
praisal vs. view contrast for negative images and (B) the respective % signal change. (C)
The difference in % signal change between the reappraisal and view conditions corre-
lated negatively with habitual reappraisal use in the CERQ (r=−.30, pb.05), which
(D) was also decreased in MDD patients (t(46)=2.6, pb.05). For graphical display
MRIcroN (http://www.cabiatl.com/mricro/mricron/index.html) was used with the
MNI template brain.
P. Kanske et al. / NeuroImage 61 (2012) 686–693
patients during reappraisal of negative emotional stimuli and in-
creased activation in the dmPFC/ACC during distraction from nega-
tive stimuli (see Fig. 4).
Comparing MDD patients and controls in the Cognitive Emotion
Regulation Questionnaire (CERQ; Garnefski and Kraaij, 2007) sub-
scales yielded a number of significant differences including the habit-
ual use of positive reappraisal (for a complete list of the scales see
Table 2). As hypothesized, patients reported less reappraisal use
than HCs (see Fig. 3). To test the relation of habitual reappraisal use
to the observed impairment in amygdala regulation in MDD patients,
we correlated individual scores of all participants in positive reap-
praisal to the down-regulation in BOLD activity in the amygdala due
to reappraisal. Here we found a negative correlation, indicating that
participants high in habitual reappraisal show a stronger down-
regulation of amygdala activity to negative images using reappraisal.
A logistic regression confirmed that the correlation was independent
of participants group (p>.80). There were no significant correlations
with activity in the control networks. As an approximation to measur-
ing competencies in distraction, we used the Adult Temperament
Questionnaire (ATQ; Rothbart et al., 2000), including the scale
attentional control, measuring the capacity to focus attention as
well as to shift attention when desired. Here, MDD patients scored
significantly below HCs (see Table 2), but there were no correlations
with brain activity (p>.20).
We found no significant correlations with any of the measures of
current symptoms including BDI, HAMD, and ADS (all p>.10). In
the patient group only, we also tested for correlations with clinical
characteristics. There were no correlations with the number of previ-
ous episodes, time since the last episode, number of hospitalizations
or age at first hospitalization, and age at the onset of the disease (all
The present results yield new insights into the crucial role of emo-
tion regulation deficits in depression. We extend previous findings of
impaired down-regulation of amygdala activity in currently symp-
tomatic MDD patients to the remitted state. We also show that this
amygdala effect is specific to reappraisal and not general to all emo-
tion regulation strategies. Interestingly, to achieve amygdala down-
regulation, patients show compensatory hyperactivation in the re-
spective regulatory network for both emotion regulation strategies
tested here, reappraisal and distraction. Furthermore, we find that
these alterations are selectively present for negative, but not positive
emotions, and are related to differences in habitual reappraisal use in
depression. The observed impairment of amygdala regulation in de-
pression did not translate to the subjective emotional state ratings.
Patients reported similar decreases in current emotion as healthy
controls. This underscores the importance of sensitive measures like
fMRI to detect changes in emotion regulation mechanisms that are
not overtly observable during remission.
A number of questionnaire studies have described emotion regu-
lation impairments as crucial factors in the development and mainte-
nance of depression (Aldao et al., 2010; Garnefski and Kraaij, 2007;
Gross and John, 2003). Habitual reappraisal use seems to be negative-
ly related to depressive symptoms, while rumination, catastrophizing,
or suppression are increased in depressed patients (Garnefski and
Kraaij, 2007; Gross and John, 2003). Our questionnaire data replicate
this pattern and further demonstrate, that low habitual use of positive
reappraisal, as present in MDD patients, is also related to less success-
ful down-regulation of amygdala activity when using reappraisal in
the experimental setting. This result bridges the gap between emo-
tion regulation in everyday life and in neuroimaging experiments. It
is in line with data from a simple emotional viewing paradigm that
also observed a negative relation of amygdala activity and habitual
reappraisal (Drabant et al., 2009).
It is interesting that patients do not show increased levels of
amygdala activity during viewing of emotionally negative stimuli, as
some studies reported this effect (Siegle et al., 2007; Surguladze et al.,
2005). Others, however, did not find elevated amygdala responding
to emotional stimuli (Beauregard et al., 1998; Frodl et al., 2009),
including the two studies on emotion regulation in depression that
also presented a neutral reference condition (Beauregard et al.,
2006; Erk et al., 2010). Lee et al. (2007) also found no direct increase
of amygdala activity, but a correlation with symptom severity, which
might explain the discrepancy. A critical difference between these
and the present study is that they investigated patients with a current
episode of major depression, while only remitted patients were
included here. A study by Sheline et al. (2001) could show that the
elevated amygdala responding during an episode is normalized after
treatment, which is in line with the lack of a difference in amygdala
activity in the viewing condition in the present study and suggests
that it is a state-, not a trait-marker of depression.
The finding of deficient regulation of amygdala activity in remitted
MDD patients with no or only mild subclinical symptoms extends the
previous data on impairments in currently depressed patients
Fig. 4. Increased activation in the regulatory control networks in MDD patients com-
pared to healthy controls during (A, C) reappraisal in the right OFC (x=30, y=44,
z=−11, Cs=35, T=3.91, Z=3.6) and (B, D) distraction in the left dmPFC (x=−6,
y=26, z=40, Cs=167, T=3.9, Z=3.6). For graphical display MRIcroN (http://
www.cabiatl.com/mricro/mricron/index.html) was used with the MNI template brain.
Means and standard deviations (in parentheses) of the CERQ and ATQ subscales in each
group are displayed. Significant differences are marked with an asterisk.
Putting into perspective
Refocus on planning
P. Kanske et al. / NeuroImage 61 (2012) 686–693
(Beauregard et al., 2006; Erk et al., 2010; Johnstone et al., 2007). It
suggests that the difficulties in regulating negative emotions are one
of the critical factors that make remission such a vulnerable state
with relatively high relapse rates (Hardeveld et al., 2010). It is an in-
teresting question that remains to be tested, if the deficits are directly
predictive of subsequent recurrence measures. The independence of
emotion regulation impairments from current MDD symptomatology,
symptom severity, and clinical characteristics identifies them as trait-
rather than state-markers of the disorder. As such, it might also be a
useful vulnerability marker of major depression that allows earlier
detection of MDD diagnosis; however, this has to be tested in unaf-
fected high-risk individuals (e.g., first-degree relatives of MDD
The present data also show that different emotion regulation
strategies are differentially affected in depression. As suggested by
previous results on emotion regulation in symptomatic MDD patients,
reappraisal is impaired, which is evident in reduced amygdala down-
regulation (Beauregard et al., 2006) and altered activity in the regula-
tory network (Erk et al., 2010; Johnstone et al., 2007). We only found
deficient amygdala down-regulation when patients used reappraisal
to regulate emotions but not when using a distraction strategy. Inter-
estingly, in healthy participants, distraction has been shown to yield a
stronger and more extended down-regulation of the amygdala re-
sponse to emotional stimuli (Kanske et al., 2011; McRae et al.,
2010), which also seems to hold true for remitted MDD patients.
However, activation in the control network was enhanced during
both strategies. Here we found hyperactivation in the dmPFC for dis-
traction and the OFC for reappraisal, brain regions that were previ-
ously identified to be selectively engaged in the respective emotion
regulation strategies (Kanske et al., 2011). In line with a number of
studies on cognitive control, this enhanced control-related activation
can be interpreted as a decrease in neural efficiency (e.g. Gray et al.,
2005). Neural inefficiency is typically characterized by enhanced
task-related neural activation, either in the absence of any behavioral
effects, or associated with poorer performance (Callicott et al., 2000;
Wagner et al., 2006). The activation increase is thought to be (partial-
ly) compensatory, thus preventing (further) behavioral deficits. In
addition to the behavioral data, in emotion regulation studies the ac-
tivity of the amygdala also serves as a measure of regulation success
(Kalisch, 2009). Therefore, the results for the two regulation strate-
gies tested here suggest that depressed participants require addition-
al neural resources to perform the regulation tasks. For distraction, a
complete compensation is possible as amygdala activity and emotion-
al state ratings do not differ between patients and controls. For reap-
praisal, in contrast, no amygdala down-regulation was observed.
Unlike the dmPFC hyperactivation during distraction, the OFC activa-
tion increase, thus, seems not to compensate amygdala control under
negative emotional stimulation. As in our previous study, this sug-
gests that the regulatory effects of distraction are more robust than
during reappraisal (Kanske et al., 2011). The psychological differences
between the strategies could give an explanation for this differentia-
tion as distraction involves shifting attention away from the emotion-
al content of the stimuli, while reappraisal requires focusing on these
aspects in order to reinterpret their meaning. This potentially leads to
stronger activation in the ventral emotional stream for the reapprai-
sal as compared with the distraction condition, making it more diffi-
cult to reduce the activity. Furthermore, even though the two
strategies are not perceived as differently difficult, there are more
possible reinterpretation options that could be generated during
reappraisal, than solutions for the arithmetic problems that need to
be generated during distraction, i.e. the reappraisal task is by defini-
tion less strongly specified and also less directive, which might be a
particular challenge for MDD patients. In addition, the respective neu-
ral networks underlying the two strategies might suffer different de-
grees of structural changes in depression, which have been more
consistently reported for the OFC than the dmPFC (for a meta-
analysis see Arnone et al., 2012). Even though MDD patients are
able to down-regulate amygdala activity during distraction, the in-
creased dmPFC activity shows that this strategy can also not be ap-
plied normally. This result corresponds to studies showing impaired
cognitive inhibition in tasks like the Stroop or Wisconsin Card Sorting
Test (Gohier et al., 2009), which have been shown to also correlate
with temperamental effortful and attentional control as measured in
the present study (Rueda et al., 2005). In a recent model, Joormann
(2010) suggested that this cognitive deficit might underlie impaired
emotion regulation through unsuccessful prevention of negative
emotion entering and remaining in working memory.
Despite the similarities of the present data and previous results on
emotion regulation through reappraisal in symptomatic MDD patients,
there are also a number of differences. Only one of the three currently
publishedstudiesfound deficientdown-regulationof amygdala activity
that we observed in remitted patients (Beauregard et al., 2006).
Johnstone et al. (2007) reported altered connectivity of amygdala and
vmPFC during reappraisal, but no direct amygdala activity difference
between patients and controls. This is most probably due to differences
in the applied experimental design, as the authors also failed to find
reduced amygdala activity during reappraisal in healthy controls and
in other samples (Urry et al., 2006). In contrast, Erk et al. (2010)
reported amygdala down-regulation in healthy participants, but – as
Johnstone et al. – did not observe alterations in MDD patients. They
found, however, lasting amygdala down-regulation in controls when
confronted with the emotional material again, while patients showed
no lasting regulation effects. A possible reason for the discrepancy to
the present study might lie in the different treatment of medication.
Erk et al. (2010) included medicated patients, but did not control for
medication in the analyses, whereas we included medication load as a
covariate in all analyses. It may, therefore, be that medication
normalizes amygdala activityduringreappraisal, a questionthatshould
be directly tested in future studies including large enough subsamples
of unmedicated and medicated patients.
The present data also show a selective deficit in regulating nega-
tive emotions. Regarding positive emotion, neither amygdala activity,
nor activation in the regulatory networks was altered during reap-
praisal or distraction when comparing MDD patients to controls.
This adds to our understanding of emotion regulation in depression
as all previous studies only reported data from negative emotional
stimuli (Beauregard et al., 2006; Erk et al., 2010; Johnstone et al.,
2007). It is a plausible result given that depression is a disorder dom-
inated by negative affect and related symptoms of low self-esteem
and loss of interest and pleasure in activities. In contrast to the unaf-
fected down-regulation of positive emotion, there is evidence that
MDD patients have problems in enhancing or sustaining positive af-
fect using cognitive emotion regulation (Heller et al., 2009). In future
studies it would be interesting to directly contrast the up- and down-
regulation of emotion in depressed patients, which might yield re-
verse patterns for positive and negative affect.
Regarding the clinical relevance of the present results, they under-
line the importance of addressing emotion regulation deficits in psy-
chotherapeutic interventions. As the deficits are not only present in
currently depressed patients, but persist when patients recover,
they are a continuing vulnerability factor and suitable treatment
may have the potential to reduce relapse rates. Because of the docu-
mented advantageous effects of reappraisal, for instance on well-
being (Gross and John, 2003), and the observed deficit in reappraisal
in particular, this strategy should be a focus of treatment. Neverthe-
less, as patients are well able to use distraction to regulate emotions,
and as distraction has been shown to have strong effect on amygdala
activity (Kanske et al., 2011; McRae et al., 2010), this strategy could
proof useful to manage states of immediate intense negative emotion.
Using reappraisal enhances the memory for regulated stimuli, which
is an indicator of its potential for long-term effects (Dillon et al.,
2007). Future studies should specify the long-term emotion
P. Kanske et al. / NeuroImage 61 (2012) 686–693
regulatory effects of both strategies to further guide psychotherapeu-
There are some limitations to the present study. As described
above, the remitted patients kept receiving optimal antidepressant
medication (9 of 23) to prevent withdrawal or emergence of depres-
sive symptoms. However, this does not allow testing the “pure” dis-
ease effects. We tried to control for this by including a composite
medication load measure as a covariate in all analyses (Sackeim,
2001). Future studies should aim at assembling larger sample sizes
that allow direct contrasts of medicated and unmedicated patients
or even of subgroups with different medication. Larger sample sizes
would also be desirable to validate the correlational results of ques-
tionnaire measures and brain activation. A further point is the speci-
ficity of the observed emotion regulation deficits to depression. A
number of questionnaire studies showed altered emotion regulation
across different diagnoses (Berking et al., 2008) and there is also
some indication that these deficits can be observed on the neural
level in different diagnoses (Modinos et al., 2010; Schulze et al.,
2011). It is a possibility that impaired emotion regulation is a truly
transdiagnostic issue. However, previous studies mainly applied
reappraisal as regulation strategy and often only include negative
emotional stimuli. Therefore, it might also be possible to differentiate
patient groups when testing different emotion regulation strategies,
responses to emotional stimuli of different valence separately, and
complex patterns of hypo- and hyperactivations in limbic and in con-
To conclude, our findings suggest that individuals with major de-
pression suffer from a deficit in down-regulating negative emotions
that extends into remission. These results are consistent with the hy-
pothesis that impaired emotion regulation is a trait-marker for de-
pression, which underscores the importance of addressing emotion
regulation as specific treatment target. The data also show the need
for future studies that assess the success of therapeutic interventions
on a neural basis and specify underlying treatment mechanisms.
We wish to thank Johanna Forneck and Heike Schmidt for help
with the data acquisition and two anonymous reviewers for their
helpful comments on a previous version of this manuscript.
The present work was funded by a grant from the Deutsche For-
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